This project proposes to systematically study the conformational structure of various analogues of serotonin (5-hydroxytryptamine, 5-HT) in relation to their possible agonist and/or antagonist properties at 5-HT receptors. To this end a variety of rigid analogues patterned after the known tetrahydropyridylindoles, RU28253 and RU24969, and/or 5-HT will be synthesized and evaluated for activity in ligand-binding assays for 5-HT receptors and in tests for functional 5-HT receptors. Ligand binding tests will include those for tryptaminergic (putative), alpha1-adrenergic and dopaminergic receptors as well as those for 5-HT-1 and 5-HT-2 receptors. Tests for functional 5-HT receptor activity will include the use of various vascular preparations (e.g., canine basilar artery and rat femoral artery), behavioral tests (e.g., 5-HT behavioral syndrome and head twitch in rats), and biochemical experiments (5-HT sensitive adenylate cyclase). The goal of the project will be to determine the conformation(s) required for the actions of 5-HT at various types of 5-HT receptors. It is also possible that new 5-HT receptor antagonists will be discovered and that both 5-HT agonists and antagonists with greater selectivity will result from this study.